The team of researchers hailed from the International AIDS Vaccine Initiative (IAVI), the Scripps Research Institute, Theraclone Sciences and Monogram Biosciences Inc.

Science Speaks interviewed one of the paper’s co-authors, Wayne C. Koff, PhD, on this exciting new science to get a better grasp on the thinking behind broadly neutralizing antibodies (bNAbs) and the AIDS vaccine development process. Internationally recognized as an expert in the field of AIDS vaccine science, Koff supervises research and development at IAVI, leading vaccine discovery programs focused on addressing the major scientific challenges impeding AIDS vaccine development, and directing IAVI’s product development programs, which have advanced six vaccine concepts to clinical trials.

Can you explain in Layman’s terms what your article in Nature found and why it is significant for HIV vaccine research? When one thinks about our best vaccines, for example polio or measles, they generally work by stimulating the immune system to produce antibodies, which bind onto the pathogen or virus and eliminate or “neutralize” it. In the case of HIV, one of the major challenges is that HIV is really variable. The virus is different all over the world, so a vaccine has to elicit antibodies that are “broadly neutralizing,” or capable of stopping a variety of HIV subtypes from infecting their target cells.

Since HIV is variable worldwide, vaccine designers attempt to identify the areas on the virus itself that are commonly vulnerable, independent of which variant of the virus it is. The ideal HIV vaccine would elicit neutralizing antibodies against all of these variable viruses.

So in this study here we, together with our collaborators, identified these broadly neutralizing antibodies (bNABs) that are not only really broad but are extremely potent – which means very low concentrations of the antibodies will be able to neutralize HIV . That’s important because with a vaccine you want to stimulate whatever level of antibodies are needed for a protective effect and you also want to maintain that effect over many years. For example, a polio vaccine is effective over a number of years, although you might need a booster every few years.

How does this tie into the research announced by the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases at the National Institutes of Health last week, which traced in detail how certain powerful neutralizing antibodies evolve? Since the early part of 2009, studies with our partners and multiple collaborators have focused on identifying the vulnerable sites on the outer protein of HIV We need this information on the molecular level so that during the vaccine design process, one tries to mimic the shape of these vulnerable sites as part of the vaccine being designed. .

These studies have now helped to identify what a map of this outer spike protein of HIV looks like, and where the vulnerable sites seen by broadly neutralizing antibodies are located.

The work led by the Vaccine Research Center scientists has focused on one of these vulnerable sites on the HIV envelope spike protein, and analyzed the evolution of broadly neutralizing antibodies to this site, referred to as the CD4 binding site, which is the site where HIV first interacts with host T cells via the CD4 receptor on the surface of the T cell. By understanding the evolution of these broadly neutralizing antibodies, vaccine designers can develop immunization strategies aimed at eliciting broadly neutralizing antibodies. Thus, the studies are quite complementary–the study in Nature identified new, potent and broadly neutralizing antibodies targeting a new vulnerable site on HIV, while the VRC study focused on neutralizing antibodies that target the CD4 binding site with an eye toward understanding their evolution. Moreover, together the studies have revealed that combinations of neutralizing antibodies that target more than one vulnerable site on HIV provide the greatest breadth of neutralization against HIV, and would be one of the goals to achieve with an HIV vaccine.

What does this mean for vaccine research? Is there a timeline that you are working from between this discovery and the development of a testable vaccine candidate? It’s really a four stage process. First is the identification of the target. What is the target on the virus that is the target of the neutralizing antibodies – and where on this target are the vulnerable sites? We’ve understood for a long time that the outer spike protein of HIV was the target for neutralizing antibodies, and these studies have now identified the vulnerable sites on this protein targeted by the antibodies.

Second is to identify at the molecular level, what is the shape is of these vulnerable sites. You can think about it with an analogy of a lock and key, where the antibodies are the locks and the vaccine will need to mimic the shape of the binding sites (the keys) to elicit these antibodies. Studies now at the molecular level are providing us with insights into the exact shape of the binding sites on HIV for the broadly neutralizing antibodies. This information will be the precursor to vaccine design.

Third and where we are now, with all of this knowledge on the CD4 binding site and the sites identified in this and previous papers, we ask our vaccine designers to design candidates capable of mimicking the shape of these binding sites, and testing biochemically in the laboratory how close the candidates are to the exact shape of the binding site. We do this by binding the broadly neutralizing antibodies to the candidate vaccines, with those candidates able to bind the antibodies the best then advancing to the next stage of testing.

The fourth step is actually making and testing the candidate vaccines. We test initially in small animals to see if we elicit the right response, then we move successful candidates on to testing in non-human primates. If they are safe and immunogenic, then we would advance them into clinical trials to look at the safety, immunogenicity and eventually the efficacy.

There only have been three vaccine approaches in the last 28 years – since HIV was identified as the cause of AIDS – that have completed the three phases of clinical trials: safety, immunogenicity and efficacy trials.. Recently there is a renaissance in the overall vaccine field, in part because of the advances in the arena of broadly neutralizing antibodies. So I suspect that we and others will begin to select a series of candidates in this calendar year and begin testing in small animals and non- human primates. And depending on the data that comes out of those trials, you would see in a few years certain candidates entering into human clinical trials.

When did IAVI launch its global search for bNAbs? In 2002, when we looked over the state of the HIV vaccine field, we identified one of the gaps in the field as a lack of a concentrated effort aimed at solving this real challenge in vaccine development, which is the broadly neutralizing antibody challenge – the ability to elicit broadly neutralizing antibodies with an HIV vaccine.

IAVI set up a consortium of scientists that we termed the Neutralizing Antibody Consortium, which has now grown to be the largest effort in the world that is focused on this one problem. We now have 18 labs worldwide that are working in this consortium, and we have also established the central hub at The Scripps Research Institute – a number of the people who worked on this paper work at that Scripps location. We started the clinical effort in about 2006 to identifying HIV-positive individuals with broadly neutralizing antibodies, and beginning with the papers on elite neutralizers and new broadly neutralizing antibodies in 2009, the last couple of years has really led to a great expansion in our knowledge about how HIV stimulates the immune system to generate broadly neutralizing antibodies. With this knowledge, we really think we are poised at the renaissance in vaccine design to elicit bNAbs, and that the antibodies that have been identified by our Consortium and by others have really generated a lot of momentum to HIV vaccine design.

This is really an exciting time and we expect that there will be a series of other papers that will emerge in the next weeks and months that will build on these results here, and the VRC paper last week, and will move us further and faster in the direction of success.

Do these bNAbs come from people who are infected with HIV but whose immune systems are not compromised by the infection? These antibodies are from individuals that have been HIV infected for at least three years, and the reason that we only looked for individuals that had been infected for at least three years is that in previous inspections we hadn’t found bNAb in people who had been infected for less than three years.. These antibodies were identified across individuals with different levels of progression to AIDS. Whether or not these antibodies will have therapeutic benefit for those HIV infected remains to be tested. However, previous testing of neutralizing antibodies, not quite as potent as these, has not provided therapeutic benefit. This is not unexpected, in that HIV is a highly mutating virus, and the virus finds ways to escape around a single antibody.

However, with a vaccine, we would aim to arm the immune system in advance, so that the broadly neutralizing antibodies are prepared to block infection at the time of exposure to the virus.